The molecule targeted antitumor drug is becoming a hot spot in new drug research and development and a new generation product during marketization after cytotoxic agents as antitumor drugs. Bcl-2 protein is the most important molecular target for antagonizing and reversing the immortality of malignant tumors. Therefore, specific antagonizing Bcl-2 protein will achieve the goals of anticancer therapy with high selectivity, safety, high performance and low painfulness by inducing intently apoptosis in tumor cells. Among Bcl-2 inhibitors, BH3 analogues (BH3 mimetics) with high selectivity exhibit the most remarkable antitumor effect, the best pharmacodynamic activity and the lowest toxic side effects. In addition, such inhibitors also must possess broad spectrum antagonizing ability on the anti-apoptotic members (including Bcl-2, Bcl-xL and Mcl-1 proteins) of the Bcl-2 family in order to gain single-agent efficacy and limited resistance.
However, until now, there are still no marketed antitumor products using Bcl-2 as target. Among the existing 19 pre-clinical Bcl-2 inhibitors, 3 optimal products are in phase I, phase II and phase III clinical trials respectively, they are ABT-737 researched and developed by Abbott Laboratories, Illinois, USA; Obatoclax (GX15-070) researched and developed by Gemin X; and AT-101 researched and developed by Ascenta in USA. They all are BH3 analogues. The competitive binding constant is up to grade nM with Bcl-2 protein, which is far higher than other 15 similar molecules. However, they all have the following deficiencies: the BH3 analogous level of Gossypol and Obatoclax is insufficient, they are not the authentic BH3 analogue, in other words, they possess cytotoxicity independent on BAX/BAK. This indicates that other target points exist, thus they have toxic side effects. Although ABT-737 is the authentic BH3 analogue, it cannot bind with Mcl-1 and cannot inhibit the Bcl-2 family proteins with broad spectrum, thereby severely limiting its application scope.
The present inventors disclosed a series of acenaphtho heterocyclic compounds of 8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile, and disclosed that these compounds had the activity of inhibiting tumor growth through inducing cell apoptosis (Chinese patent, Authorized Announcement No. CN1304370C). However, as a potential antitumor drug on basis of apoptosis, its research and development faces the same difficulties as the similar drugs: the complexity of apoptosis signal gateway, the potential and intensive cytotoxicity as well as the inevitable blindness resulted from taking medicine. All of these are the important reasons for the failure in the development of such similar drugs. Therefore, the targeting effect of drugs should be prominently emphasized in the research course.